Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial

The current standard of care for muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC) and perioperative systemic therapy despite their well-known  potential for significant complications, adverse events, and impact on quality of life (QoL) due to the need for a urinary diversion. However, neoadjuvant cisplatin-based chemotherapy and transurethral resection of bladder tumour (TURBT) alone may achieve a complete pathologic response (pCR) in up to 30-40% of the cases, raising questions about the necessity of immediate RC for all patients.

Challenges in the validation of such hypothesis comes from the heterogeneity of the available literature. In particular, these include a lack of prospective studies and standardised approaches to measure clinical complete response (cCR). Additionally, the best possible neoadjuvant setting including single-agent PD-1/PD-L1 immune checkpoint blockade, alone or with cisplatin, to achieve cCR is still under investigation. Molecular biomarkers, specifically DNA damage repair (DDR) gene alterations, may enhance patient selection for TURBT plus systemic therapy.

The recently published work from Galsky et al explores various clinical backgrounds. The phase 2 trial incorporates cisplatin-based chemotherapy, PD-1 blockade (i.e., Nivolumab), standardised cCR assessment following TURBT and DDR biomarker analyses to tailor optimal responders. Specifically, the co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival (MFS) in patients forgoing immediate RC or <ypT1N0 in patients electing immediate RC.

Methodology summary

• Clinical restaging comprised of magnetic resonance imaging (MRI) of the abdomen and pelvis, CT of the chest, cystoscopy with biopsies according to a recommended template, and urine cytology.
• AcCR was defined as (1) no evidence of high-grade malignancy on biopsy; (2) no malignant cells on urine cytology; and (3) no definitive evidence of local or metastatic disease on cross-sectional imaging.
• Patients achieving a cCR were offered the option to proceed with RC vs. retain their bladder and receive eight additional doses of nivolumab (administered every 2 weeks) followed by surveillance. Patients not achieving a cCR were recommended to proceed with cystectomy.

Results summary – primary and secondary endpoints:

• The co-primary endpoint of cCR was achieved in 33 of 76 patients (43%, 95% confidence interval (CI): 32%, 55%). Among the 33 patients achieving a cCR, only one opted for upfront RC and the positive predictive value of cCR for the composite outcome measure was 0.97 (95% CI: 0.91, 1), reaching the prespecified statistical threshold of the lower bound CI set at 0.80%. Furthermore, the median MFS and overall survival (OS) for the entire study cohort was not reached at the time of the data lock (secondary endpoints), yet on landmark analysis from the time of restaging, patients achieving a cCR experienced significantly longer MFS and OS compared to patients not achieving a cCR.
• Tolerability and safety profile was acceptable with grade ≥3 treatment-emergent adverse events occurred in 75% of patients. The most common all-grade adverse events were fatigue, anaemia, neutropenia and nausea, and the most common grade ≥3 treatment-emergent adverse events were anaemia, neutropenia and urinary tract infections.
• In the study’s secondary objective, Galsky and colleagues, aimed to evaluate whether specific genomic alterations in baseline TURBT tissue could improve the positive predictive value of clinical complete response (cCR) for the composite outcome of 2-year MFS. Tumour-only targeted DNA sequencing was conducted on pre-treatment TURBT tissue from 73 out of 76 patients. A panel of genes associated with response to cisplatin-based chemotherapy or PD-1/PD-L1 blockade (ERCC2, RB1, ATM, and FANCC), along with increased tumour mutational burden (TMB), was analysed. However, due to the high positive predictive value of cCR alone, the intended assessment was not feasible. Instead, the study explored the impact of adding pre-specified genomic alterations to cCR on the composite outcome of 2-year bladder-intact survival. The results indicated that the addition of these genomic alterations did not significantly enhance the positive predictive value of cCR alone, except for a potential association between pathogenic RB1 mutations and a cCR, observed in five patients. An exploratory analysis also suggested higher cCR rates in patients with tumours harbouring ERCC2 mutations or TMB ≥10 mut/Mb, although statistical significance was not reached after correction for false discovery.

Regarding imaging outcomes in the assessment of cCR, post-cycle-4 restaging involved MRI scans in 50 of 76 patients. Exploratory analysis using vesical imaging-reporting and data system (VI-RADS) scores revealed that a VI-RADS score of ≤2 versus >2 at restaging was significantly associated with longer MFS (P = 0.0002).

Additionally, these are the following results highlighted regarding the immunological features assessed as part of the translational attempt:

• PD-L1 expression: Higher PD-L1 combined positive scores in baseline TURBT specimens correlated with a higher (cCR) rate, although this did not significantly impact MFS or OS.
• Immune cell abundance: Specific immune cell populations correlated with achieving a cCR, but statistical significance was not reached after correction for false discovery.
• Naive CD4+ and CD8 T cells: Higher abundance of naive CD4+ T cells on cycle 1, day 1, and naive CD8 T cells on cycle 3, day 1, was associated with significantly longer MFS and OS.
• Plasma protein analytes: Levels of TRAIL, FasL, and CD244 in plasma on cycle 3, day 1 were significantly higher in patients achieving a cCR. Higher levels of IL6 and ANGPT2 on cycle 1, day 1 were associated with shorter MFS and OS.
• Urine analytes: No urine analytes at clinical restaging were significantly associated with achieving a cCR. Increased urine levels of EGF at clinical restaging were associated with inferior MFS and OS.

The study acknowledges certain limitations, including the need for longer-term follow-up to fully comprehend the impact on disease control. The question of whether all patients achieving a cCR should undergo (chemo)radiation for optimal bladder preservation and the complex interplay of organ preservation, cancer control, and potential overtreatment require further investigation. Patient-reported outcome data, although not collected in this study, would provide essential additional context.

Take home messages of the HCRN GU16-257 Trial

• Innovative treatment approach: This study introduces a novel approach, utilising TURBT, cisplatin-based chemotherapy, and immune checkpoint blockade for bladder-sparing treatment of MIBC.
• cCR significance: Rigorously defined cCR is associated with favourable survival outcomes, emphasising its potential as a crucial tool for patient selection in this treatment strategy.
• Balancing efficacy and survivorship: The study highlights the importance of risk-adapted treatment paradigms that balance treatment efficacy and patient survivorship while minimising treatment-related burdens.
• Cisplatin and immune checkpoint blockade synergy: The combination of cisplatin with immune checkpoint blockade demonstrates promising results, suggesting unique immunomodulatory effects of cisplatin that may contribute favourably to treatment outcomes.
• Challenges and further investigation: Questions regarding the necessity of (chemo)radiation for all patients achieving a cCR and the potential impact on organ preservation, cancer control, and overtreatment warrant further investigation. Patient-reported outcomes and longer-term follow-up data will provide valuable insights.
• Refining treatment paradigms: Genomic, imaging, and immunological biomarkers have the potential to refine and personalise MIBC management, paving the way for more tailored approaches in the future.